Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1995-12-20
2002-08-06
Romeo, David S. (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069700, C435S252300, C435S320100, C435S325000, C435S458000, C530S350000, C530S333000, C530S333000, C530S333000, C530S333000
Reexamination Certificate
active
06428977
ABSTRACT:
FUNDING
Work described herein was supported by funding from the National Institutes of Health. The United States Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation (Davidson, E., (1990)
Development
108: 365-389; Gurdon, J. B., (1992)
Cell
68: 185-199; Jessell, T. M. et al., (1992)
Cell
68: 257-270). The effects of developmental cell interactions are varied. Typically, responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions). Sometimes cells induce their neighbors to differentiate like themselves (homoiogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself. Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity. Moreover, inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation (J. B. Gurdon (1992)
Cell
68:185-199).
Several classes of secreted polypeptides are known to mediate the cell-cell signaling that determines tissue fate during development. An important group of these signaling proteins are the TGF&bgr; superfamily of molecules, which have wide range of functions in many different species. Members of the family are initially synthesized as larger precursor molecules with an amino-terminal signal sequence and a pro-domain of varying size (Kingsley, D. M. (1994)
Genes Dev
. 8:133-146). The precursor is then cleaved to release a mature carboxy-terminal segment of 110-140 amino acids. The active signaling moiety is comprised of hetero- or homodimers of the carboxy-terminal segment (Massague, J. (1990)
Annu. Rev. Cell Biol
. 6:597-641). The active form of the molecule then interacts with its receptor, which for this family of molecules is composed of two distantly related transmembrane serine/threonine kinases called type I and type II receptors (Massague, J. et al. (1992)
Cell
69:1067-1070; Miyazono, K. A. et al.
EMBO J
. 10:1091-1101). TGF&bgr; binds directly to the type II receptor, which then recruits the type I receptor and modifies it by phosphorylation. The type I receptor then transduces the signal to downstream components, which are as yet unidentified (Wrana et al, (1994)
Nature
370:341-347).
Several members of the TGF&bgr; superfamily have been identified which play salient roles during vertebrate development. Dorsalin is expressed preferentially in the dorsal side of the developing chick neural tube (Basler et al. (1993)
Cell
73:687-702). It promotes the outgrowth of neural crest cells and inhibits the formation of motor neuron cells in vitro, suggesting that it plays an important role in neural patterning along the dorsoventral axis. Certain of the bone morphogenetic proteins (BMPs) can induce the formation of ectopic bone and cartilage when implanted under the skin or into muscles (Wozney, J. M. et al. (1988)
Science
242:1528-1534). In mice, mutations in BMP5 have been found to result in effects on many different skeletal elements, including reduced external ear size and decreased repair of bone fractures in adults (Kingsley (1994)
Genes Dev
. 8:133-146). Besides these effects on bone tissue, BMPs play other roles during normal development. For example, they are expressed in non skeletal tissues (Lyons et al. (1990)
Development
109:833-844), and injections of BMP4 into developing Xenopus embryos promote the formation of ventral/posterior mesoderm (Dale et al (1992)
Development
115:573-585). Furthermore, mice with mutations in BMP5 have an increased frequency of different soft tissue abnormalities in addition to the skeletal abnormalities described above (Green, M. C. (1958)
J. Exp. Zool
. 137:75-88).
Members of the activin subfamily have been found to be important in mesoderm induction during Xenopus development (Green and Smith (1990)
Nature
47:391-394; Thomsen et al. (1990)
Cell
63:485-493) and inhibins were initially described as gonadal inhibitors of follicle-stimulating hormone from pituitary cells. In addition, antagonists of this signaling pathway can be used to convert embryonic tissue into ectoderm, the default pathway of development in the absence of TGF&bgr;-mediated signals. BMP-4 and activin have been found to be potent inhibitors of neuralization (Wilson, P. A. and Hemmati-Brivanlou, A (1995)
Nature
376:331-333).
Further evidence for the importance of a TGF&bgr; family member in early vertebrate development comes from a retroviral insertion in the mouse nodal gene. This insertion leads to a failure to form the primitive streak in early embryogenesis, a lack of axial mesoderm tissue, and an overproduction of ectoderm and extraembryonic ectoderm (Conlon et al. (1991)
Development
111:969-981; lannaccone et al (1992)
Dev. Dynamics
194:198-208). The predicted nodal gene product is consistent with previous studies showing that nodal is related to activins and BMPs (Zhou et al. (1993)
Nature
361:543-547). A role for TGF&bgr; family members in the development of sex organs has also been described; Mullerian inhibitory substance functions during vertebrate male sexual development to cause regression of the embryonic duct system that develops into oviducts and uterus (Lee and Donahoe (1993)
Endocrinol. Rev
. 14:152-164).
Members of this family of signaling molecules also continue to function post-development. TGF&bgr; has antiproliferative effects on many cell types including epithelial cells, endothelial cells, smooth muscle cells, fetal hepatocytes, and myeloid, erythroid, and lymphoid cells. Animals which cannot produce TGF&bgr;1 (homozygous for null mutations in the TGF&bgr;1 gene) have been found to survive until birth with no apparent morphological abnormalities (Shull et al. (1992)
Nature
359:693-699; Kulkarni et al. (1993)
Proc. Natl. Acac. Sci
. 90:770-774). The animals do die around weaning age, however, owing to massive immune infiltration in may different organs. These data are consistent with the inhibitory effects of TGF&bgr; on lymphocyte growth (Tada et al. (1991)
J. Immunol
146:1077-1082). In another system, the expression of a TGF&bgr; transgene in the mammary tissue of mice has been shown to inhibit the development and secretory function of mammary tissue during sexual maturation and pregnancy (Jhappan, C. et al. (1993)
EMBO J
. 12:1835-1845; Pierce, D. F. et al. (1993)
Genes Dev
. 7:2308-2317). In addition to these inhibitory effects, TGF&bgr; can also promote the growth of other cell types as evidenced by its role in neovascularization and the proliferation of connective tissue cells. Because of these activities, it plays a key role in wound healing (Kovacs, E. J. (1991)
Immunol Today
12:17-23)
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a novel family of genes, and gene products, expressed in vertebrate organisms, which genes referred to hereinafter as the “signalin” gene family, the products of which are referred to as signalin proteins. The products of the signalin gene have apparent broad involvement in the formation and maintenance of ordered spatial arrangements of differentiated tissues in vertebrates, and can be used or manipulated to generate and/or maintain an array of different vertebrate tissue both in vitro and in vivo.
In general, the invention features isolated vertebrate signalin polypeptides, preferably substantially pu
Graff Jonathan M.
Jin Ping
Melton Douglas A.
Woolf Tod M.
Curis, Inc.
Halstead David P.
Romeo David S.
Ropes & Gray
Vincent Matthew P.
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